Dyspepsia, or indigestion, is a common diagnosis in primary health care, but with poorly defined management. The annual prevalence of dyspepsia in the United Kingdom (UK) is about 25%, and in primary health care it accounts for 3–4% of the consultations (Harris, A., Eur J Gastroenterol Hepat 1999; 11 (Suppl 1): S31–5). Among the chronic disorders of the upper gastrointestinal tract are those which fall under the general category of gastritis. Gastritis is an inflammation of the stomach mucosa which is manifested by a broad range of poorly-defined symptoms such as indigestion, “heart burn” and excessive eructation. The typical means used to diagnose gastrointestinal disorders depends on such factors as the nature and severity of symptoms, the overall health of the individual, the medical history of the patient, the need for a specific diagnosis in order to implement a treatment with reasonable likelihood of success, and the availability of diagnostic devices.
Esophagogastroduodenoscopy (EGD) with histopathological examination of biopsies is the gold standard to determine the status of the gastric and duodenal mucosa. This examination is safe, accurate and sometimes indispensable, e.g., in the older age group and especially in the presence of alarm symptoms such as weight loss, anorexia, dysphagia, or gastrointestinal blood loss. The demand for upper endoscopy is increasing and in the UK approximately 0.5% of the population undergo this examination each year (Working Party of the Clinical Services Committee of the British Society of Gastroenterology, Provision of gastrointestinal endoscopy and related services for a district general hospital. Gut 1991; 32: 95–105; Gear, M. W. L., and Wilkinson, S. P., Br J Hosp Med 1989; 41: 438–44). Without EGD and visual inspection of the mucosa, gastritis is difficult to diagnose. However, EGD is expensive, inconvenient for the patient, and generally not recommended for children or patients with severe cardiopulmonary disease. Thus, for patients not having severe symptoms, a precise diagnosis of a gastrointestinal disorder might not be attempted. Such patients may simply be treated with conventional therapies, such as with antacids or drugs which inhibit stomach acid secretion. While such therapies might provide temporary relief of the symptoms, a cure is not often achieved. More effective treatments generally depend on a better diagnosis of the actual underlying gastrointestinal disorder. For example, many gastrointestinal disorders are mediated by bacterial infection of the mucosa, in which case treatment of the bacterial infection would most likely be required to effectively treat the manifested gastrointestinal disorder.
There is a need for a simple pre-gastroscopic screening method to reduce the endoscopy workload, and attempts have been made in this direction with some success in patients with uncomplicated simple dyspepsia (Bodger, K., et al., Scand J Gastroenterol 1999; 34: 856–63; and Moayyedi, P., et al., Eur J Gastroenterol Hepatol 1999; 11:1245–50). In young dyspeptic patients (<40 years) screening for Helicobacter pylori (H. pylori) infection and a treatment strategy based on the presence of an infection reduces the endoscopy workload. This strategy appears as effective as an endoscopy-based strategy in reducing dyspeptic symptoms, dyspepsia consultation rates and the prescription of anti-secretory drugs (Moayyedi, P., et al., Eur J Gastroenterol Hepatol 1999; 11:1245–50). In the elderly with dyspepsia, however, the prevalence of gastritis and its consequences are considerably higher pointing at EGD as the initial diagnostic step.
The inflamed gastric mucosa transmits specific information to the blood stream that allows diagnosis of gastritis by serologic analysis. The morphology and cellular composition of the mucosa vary between the acid secreting corpus and the antrum. This may aid to distinguish corpus and pangastritis from antral gastritis. A number of serological markers have been described. Infection with H. pylori is the major cause of chronic gastritis, duodenal ulcer, mucosa associated lymphoid tissue (MALT) lymphoma and gastric cancer (Chiba, N., et al., Can Fam Physician 1998; 44: 1481–8; Genta, R. M., Gut 1998; 43: 35–8; Coyle, W. J., et al., Gastrointest Endosc 1998; 48: 327–8; Lee, B. M., et al., Jpn J Cancer Res 1998; 89: 597–603), and antibodies to various H. pylori antigens can easily be detected in the blood (Bodger, K., et al., Scand J Gastroenterol 1999; 34: 856–63; Moayyedi, P., et al., Eur J Gastroenterol Hepatol 1999; 11:1245–50). This infection is sometimes associated with an autoimmune reaction leading to atrophy of the corpus mucosa (Ozasa, K., et al., Dig Dis Sci 1999; 44: 253–6). A common feature of gastric autoimmunity and frequently several other autoimmune diseases, e.g., thyroiditis, insulin dependent diabetes mellitus and sometimes rheumatoid arthritis, is the occurrence of parietal cell autoantibodies (Bech, K., et al., Acta Endocrinol 1991, 124: 534–9; Barrio, R., et al., Pediatr Endocrinol Metab 1997, 10: 511–6; Datta, A., et al., Indian J Med Res 1990, 92: 228–32; Mårdh, S., et al., Scand J Gastroenterol 1991, 26: 1089–96). The parietal cell H,K-ATPase Δ- and β-subunits were found to be the major autoantigens in autoimmune atrophic gastritis (Karlsson, A., et al., J Clin Invest 1988, 81: 475–9; Song, Y. H., et al., Scand J Gastroenterol 1994, 29:122–7; Ma, J. Y., et al., Scand J Gastroenterol 1994, 20: 790–4). A low titre of H,K-ATPase antibodies is normally found in healthy individuals due to the normal turn-over of parietal cells. In patients with inflamed corpus mucosa the titre may be increased.
Pepsinogen I (PGI) is secreted by the chief and mucous neck cells of the corpus mucosa into the lumen of the stomach but a small fraction (about 1%) leaks into the blood stream (Baron, J. H., Clinical tests of gastric secretion: History, Methodology and Interpretation. (1978) London: Macmillan). Increased serum concentrations of PGI are frequently found in patients with duodenal ulcer (Samloff, I. M., et al., Gastroenterol 1975 July, 69(1): 83–90). In patients with pernicious anaemia due to severe atrophy of the corpus mucosa serum PGI is significantly reduced (Samloff, I. M., et al., Gastroenterol 1982 July, 83(1 Pt 2): 204–9).
Existing, non-invasive methods of detecting gastrointestinal disorders include monitoring blood flow to the affected region to detect inflammation (U.S. Pat. No. 5,524,622). A significant disadvantage of this method is the requirement of injecting multiple substances into the patient followed by the detection by gamma camera. Additionally, the method only detects inflammation, and does not address the underlying cause of any inflammation. Other methods of detecting gastrointestinal disorders include assays for individual analytes such as pepsinogen (U.S. Pat. No. 5,879,897) or Helicobacter pylori (U.S. Pat. Nos. 5,814,455; 6,067,989; 6,068,985; 6,090,611). Other serological markers are gastrin (Borch, K., et al., Scand J Gastroenterol 1997, 32:198–202), pepsinogen II (Carmel, R., Am J Pathol 1998, 90: 442–5), intrinsic factor antibodies (Waters, H. M., et al., J Clin Pathol 1989, 42: 307–12) and pepsinogen antibodies (Mårdh, S., et al., Acta Physiol Scand 1989, 136: 581–7). Although each one of these markers may be used to diagnose changes in the gastric mucosa, the overlap between healthy subjects and patients is great, and even greater among the various subgroups of patients. Therefore none of all these markers alone is sufficient for a reliable diagnosis.